Role NR1/2C and NR1/2D NMDA Receptors in Cortex Function and Memantine Action

NR1/2C 和 NR1/2D NMDA 受体在皮质功能和美金刚作用中的作用

• 批准号: 8232064
• 负责人: Jon W. Johnson
• 金额: $ 18.6万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-03-01 至 2014-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8232064
• 关键词: Adult; Affect; Affinity; Alzheimer' s Disease; Animal Behavior; Animal Model; Animals; Behavioral; Brain; Brain region; Cells; Cessation of life; Characteristics; Clinical; Coupled; Data; Disinhibition; Dose; Drug usage; Epilepsy; Excitatory Synapse; Exhibits; FDA approved; Functional disorder; Genes; Genetic; Glutamate Receptor; Glutamates; Goals; Health; Hippocampus (Brain); Huntington Disease; Impaired cognition; Interneurons; Knockout Mice; Lead; Learning; Location; Measures; Mediating; Memantine; Memory; Mental Depression; Messenger RNA; N-Methyl-D-Aspartate Receptors; N-Methylaspartate; NMDA receptor 2B; NMDA receptor antagonist; NR1 gene; Neocortex; Nervous System Physiology; Nervous system structure; Neurodegenerative Disorders; Neurons; Patients; Permeability; Pharmaceutical Preparations; Physiological; Play; Postsynaptic Membrane; Property; Publications; Publishing; Pyramidal Cells; Reporting; Research; Rodent; Role; Schizophrenia; Site; Slice; Somatostatin; Synapses; Synaptic plasticity; Testing; Therapeutic; Therapeutic Effect; Work; base; design; detector; extracellular; high reward; high risk; improved; inhibitory neuron; insight; mutant; neocortical; nervous system disorder; novel; patch clamp; postsynaptic; presynaptic; prevent; receptor; research study; response; tool; voltage

DESCRIPTION (provided by applicant): Most excitatory synaptic excitation in the brain is mediated by glutamate receptors. NMDA receptors (NMDARs), a glutamate receptor subtype specifically activated by N-methyl-D-aspartate, are expressed on almost all mammalian central neurons. NMDARs exhibit high Ca2+ permeability and voltage-dependent channel block by Mg2+, characteristics that allow them to play central roles in synaptic plasticity and memory. NMDARs also are broadly involved in nervous system dysfunction, and have been implicated in many nervous system diseases including Alzheimer's disease (AD), Huntington's disease, schizophrenia, epilepsy, and depression. NMDARs are usually composed of two types of subunits, NR1 and NR2; there are four NR2 subunits encoded by separate genes (NR2A-NR2D), which, when combined with NR1, define four major NMDAR subtypes (NR1/2A - NR1/2D). The function of the NR1/2A and NR1/2B NMDAR subtypes, which are heavily expressed in adult cortex, have been extensively investigated. The function of the NR1/2C and NR1/2D NMDAR subtypes, which also are expressed in adult cortex (especially NR1/2D), although at lower levels than the other NMDAR subtypes, are less well understood. Recent data suggest that the NR1/2C and/or NR1/2D NMDARs play an especially important role in the clinical utility of the widely-used AD drug memantine, which is an antagonist of NMDARs. It appears surprising that memantine, a drug that slows cognitive decline in AD patients, would act by inhibiting NMDARs, which are essential for memory. The paradoxical therapeutic effects of memantine have been proposed to result from selective inhibition of NR1/2C and NR1/2D receptor subtypes located on cortical interneurons, resulting in cortical disinhibition. The involvement of NR1/2C and/or NR1/2D NMDARs in activation of inhibitory neurons also may be of special significance to animal models of schizophrenia. The broad objectives of this application are to uncover the roles of NR1/2C and NR1/2D NMDARs in the cortex, and to improve understanding of the mechanism of action of memantine. These objectives will be accomplished by determining: the neuronal subtypes in cortex that express NR1/2C and/or NR1/2D NMDARs; their synaptic versus extrasynaptic location; whether the receptors contribute to tonically active glutamate currents; the effects of memantine on NMDAR responses of several neuronal subtypes in cortex; how genetic deletion of the NR2D subunit affects NMDAR responses in neuronal subtypes in cortex; and the influence of NR2D subunit genetic deletion on the behavioral effects of memantine. To achieve these goals we will apply, to both wild-type and mutant rodents, a powerful combination of approaches, including electrophysiological recordings from brain slices, receptor identification with new pharmacological tools, and analysis of animal behavior. The proposed research will provide fundamental information on cortical NMDARs with broad implications for nervous system function and dysfunction, and will help explain the therapeutic mechanism of a widely used AD drug. PUBLIC HEALTH RELEVANCE: The research proposed in this application will help us understand how inhibition in the brain is controlled, and how memantine, a drug used to treat Alzheimer's disease, affects inhibition. Understanding how inhibition is controlled will provide insight into normal brain function, and possibly into the changes in brain function that cause schizophrenia. Understanding how memantine helps patients with Alzheimer's disease may lead to the design of improved Alzheimer's disease treatments.

描述（由申请人提供）：大脑中的大多数兴奋性突触兴奋由谷氨酸受体介导。NMDA受体（NMDARs）是一种由N-甲基-D-天冬氨酸特异性激活的谷氨酸受体亚型，几乎在所有哺乳动物中枢神经元上表达。NMDAR表现出高Ca 2+渗透性和Mg 2+的电压依赖性通道阻滞，这些特征使其在突触可塑性和记忆中发挥核心作用。NMDAR还广泛涉及神经系统功能障碍，并且已经涉及许多神经系统疾病，包括阿尔茨海默病（AD）、亨廷顿病、精神分裂症、癫痫和抑郁症。NMDAR通常由两种类型的亚基组成，NR 1和NR 2;有四种NR 2亚基由不同的基因编码（NR 2A-NR 2D），当与NR 1组合时，定义了四种主要的NMDAR亚型（NR 1/2A-NR 1/2D）。NR 1/2A和NR 1/2B NMDAR亚型在成人皮质中大量表达，其功能已被广泛研究。NR 1/2C和NR 1/2D NMDAR亚型也在成人皮质（尤其是NR 1/2D）中表达，尽管其水平低于其他NMDAR亚型，但其功能尚不清楚。最近的数据表明，NR 1/2C和/或NR 1/2D NMDARs在广泛使用的AD药物美金刚（memantine）的临床应用中发挥特别重要的作用，美金刚是NMDARs的拮抗剂。令人惊讶的是，美金刚，一种减缓AD患者认知能力下降的药物，将通过抑制对记忆至关重要的NMDAR来发挥作用。已提出美金刚的矛盾的治疗作用是由于选择性抑制位于皮质中间神经元上的NR 1/2C和NR 1/2D受体亚型，导致皮质去抑制。NR 1/2C和/或NR 1/2D NMDARs参与抑制性神经元的激活对精神分裂症动物模型也可能具有特殊意义。本申请的广泛目标是揭示NR 1/2C和NR 1/2D NMDAR在皮质中的作用，并提高对美金刚作用机制的理解。这些目标将通过确定：表达NR 1/2C和/或NR 1/2D NMDAR的皮质中的神经元亚型;它们的突触相对于突触外位置;受体是否有助于紧张性活性谷氨酸电流;美金刚对皮质中几种神经元亚型的NMDAR反应的影响; NR 2D亚基的遗传缺失如何影响皮质中神经元亚型的NMDAR反应;以及NR 2D亚基基因缺失对美金刚行为效应的影响。为了实现这些目标，我们将适用于野生型和突变型啮齿动物，一个强大的组合的方法，包括从脑切片的电生理记录，受体识别与新的药理学工具，和动物行为的分析。拟议的研究将提供有关皮质NMDAR的基本信息，对神经系统功能和功能障碍具有广泛的影响，并将有助于解释广泛使用的AD药物的治疗机制。 公共卫生关系：这项申请中提出的研究将帮助我们了解大脑中的抑制是如何控制的，以及用于治疗阿尔茨海默病的药物美金刚胺如何影响抑制。了解抑制是如何控制的，将有助于了解正常的大脑功能，并可能了解导致精神分裂症的大脑功能变化。了解美金刚如何帮助阿尔茨海默病患者可能会导致设计改善阿尔茨海默病治疗。